title: Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1.
abstract: BACKGROUND
  This trial describes a first-in-man evaluation of RH1, a novel bioreductive drug activated by DT-diaphorase (DTD), an enzyme overexpressed in many tumours.
  
  
  METHODS
  A dose-escalation phase I trial of RH1 was carried out. The primary objective was to establish the maximum tolerated dose (MTD) of RH1. Secondary objectives were assessment of toxicity, pharmacokinetic determination of RH1 and pharmacodynamic assessment of drug effect through measurement of DNA cross linking in peripheral blood mononuclear cells (PBMCs) and tumour, DTD activity in tumour and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphism status.
  
  
  RESULTS
  Eighteen patients of World Health Organization performance status of zero to one with advanced refractory solid malignancies were enrolled. MTD was 1430 μg/m(2)/day with reversible bone marrow suppression being dose limiting. Plasma pharmacokinetic analysis showed RH1 is rapidly cleared from blood (t(1/2) = 12.3 min), with AUC increasing proportionately with dose. The comet-X assay demonstrated dose-related increases in DNA cross linking in PBMCs. DNA cross linking was demonstrated in tumours, even with low levels of DTD. Only one patient was homozygous for NQO1 polymorphism precluding any conclusion of its effect.
  
  
  CONCLUSIONS
  RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 μg/m(2)/day is the dose recommended for phase II trials. The biomarkers of DNA cross linking, DTD activity and NQO1 status have been validated and clinically developed.
authors.affiliation: Department of Medical Oncology, University of Manchester, Christie Hospital NHS Foundation Trust, Manchester; Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research. Electronic address: s.danson@sheffield.ac.uk.
authors.forename: S J
authors.initials: SJ
authors.lastname: Danson
authors.affiliation: Cancer Research UK Clinical Centre, Southampton General Hospital, Southampton.
authors.forename: P
authors.initials: P
authors.lastname: Johnson
authors.affiliation: Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research.
authors.forename: T H
authors.initials: TH
authors.lastname: Ward
authors.affiliation: Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research.
authors.forename: M
authors.initials: M
authors.lastname: Dawson
authors.affiliation: Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research.
authors.forename: O
authors.initials: O
authors.lastname: Denneny
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester.
authors.forename: G
authors.initials: G
authors.lastname: Dickinson
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester.
authors.forename: L
authors.initials: L
authors.lastname: Aarons
authors.affiliation: Cancer Research UK Clinical Centre, Southampton General Hospital, Southampton.
authors.forename: A
authors.initials: A
authors.lastname: Watson
authors.affiliation: Department of Medical Oncology, University of Manchester, Christie Hospital NHS Foundation Trust, Manchester.
authors.forename: D
authors.initials: D
authors.lastname: Jowle
authors.affiliation: Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research.
authors.forename: J
authors.initials: J
authors.lastname: Cummings
authors.affiliation: Cancer Research UK Drug Development Office, Cancer Research UK, London.
authors.forename: L
authors.initials: L
authors.lastname: Robson
authors.affiliation: Cancer Research UK Formulation Unit, University of Strathclyde, Glasgow, UK.
authors.forename: G
authors.initials: G
authors.lastname: Halbert
authors.affiliation: Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research.
authors.forename: C
authors.initials: C
authors.lastname: Dive
authors.affiliation: Department of Medical Oncology, University of Manchester, Christie Hospital NHS Foundation Trust, Manchester; Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research.
authors.forename: M
authors.initials: M
authors.lastname: Ranson
mesh_terms: D000328:Adult; D000368:Aged; D001388:Aziridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016227:Benzoquinones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics; D012189:Retrospective Studies; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: C117776:2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone; D001388:Aziridines; D016227:Benzoquinones; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human